The title of this Program Project application is: Immunopathogenesis of Acute and Early HIV Infection. The program will consist of 4 projects supported by 2 core facilities. The program also will be supported by the infrastructures of the immunology, virology and clinical support (biostatistics-epidemiology) cores of the NYU CFAR and will rely heavily on resources within the AIDS Clinical Trials Unit. The program will be highly integrated in that some investigators will be working on more than one of the projects, and experiments will be performed in different projects on samples obtained at the same time from the same patients to facilitate interpretation of the results. All results will be entered into a common data-base developed by Frontier Science. The overall question of why strong CD4 reactivity to HIV antigens is lost or is not induced in subjects in whom treatment is delayed will be addressed in different ways by each of the projects. Immune responses control almost all viral infections that are not lethal during the first few days, yet long-term effective immunological control of HIV occurs in a small minority of infected individuals. The mechanisms by which HIV blocks the establishment of effective immune responses are not clear, but must be operative at the earliest stages of the infection. These mechanisms may include malfunctioning of the antigen presentation process by dendritic cells, inappropriate hyperactivation of T cells and apoptosis, or deletion or unresponsiveness of CD4 clones responsive to HIV antigens. Long-term nonprogressors with a low viral load maintain lymphocyte proliferative responses (LPR) to HIV antigens, a memory response, whereas the majority of individuals with established infection lack strong LPR to HIV antigens even after suppression of viral load with antiretroviral therapy. Our hypothesis is that the failure to develop and maintain memory CD4 responses to HIV antigens is a pivotal pathologic process in HIV infection. This program will take advantage of the large numbers of acute and early HIV infections being identified at NYU/Bellevue and our affiliated hospitals, combined with the large numbers of similar individuals. (At present NYU/Bellevue is tied with UCSD for top enrollment into the ACTG study of primary HIV infection.) We also will follow the cohort of individuals who are at exceedingly high risk of acute infection for whom we will have viably frozen cells obtained prior to infection should it occur.